These results provide biochemical evidence that supports a specific role of TSP-4 among the TSPs in mediating the binding to neuronal α<sub>2</sub>δ-1 and suggest that gabapentin does not directly target TSP/α<sub>2</sub>δ-1 interaction to alleviate neuropathic pain.
Up-regulation of thrombospondin-4 (TSP4) or voltage-gated calcium channel subunit α<sub>2</sub>δ<sub>1</sub> (Ca<sub>v</sub>α<sub>2</sub>δ<sub>1</sub>) proteins in the spinal cord contributes to neuropathic pain development through an unidentified mechanism.
Nerve injury induces concurrent up-regulation of the voltage-gated calcium channel subunit Ca<sub>v</sub> α<sub>2</sub> δ<sub>1</sub> and the extracellular matrix protein thrombospondin-4 (TSP4) in dorsal root ganglia and dorsal spinal cord, leading to the development of a neuropathic pain state.
Controlling TSP4 mediated intracellular Ca<sup>2+</sup> signaling in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.